U.S. patent application number 10/158811 was filed with the patent office on 2002-12-12 for conformal coated microchip reservoir devices.
Invention is credited to Feakes, Christina M., Sheppard, Norman F. JR..
Application Number | 20020187260 10/158811 |
Document ID | / |
Family ID | 23133541 |
Filed Date | 2002-12-12 |
United States Patent
Application |
20020187260 |
Kind Code |
A1 |
Sheppard, Norman F. JR. ; et
al. |
December 12, 2002 |
Conformal coated microchip reservoir devices
Abstract
Microchip devices are provided with an inert and biocompatible
conformal coating to mitigate adverse responses following device
implantation in a patient, to contain and seal a drug or other
material within the device, and/or to insulate the electrical
connections to the device. The device can include: (1) a substrate
having a plurality of reservoirs; (2) reservoir contents, such as a
drug or biosensor, in the reservoirs; (3) reservoir caps covering
the reservoirs to isolate the contents from environmental
components outside the reservoirs; and (4) a conformal coating over
the outer surface of at least a portion of the substrate other than
the reservoir caps. The reservoir caps can be selectively
disintegrated or permeabilized to expose the reservoir contents to
environmental components. The conformal coating preferably
comprises a vapor depositable polymeric material, such as parylene.
Processes for controlling coating of the devices while facilitating
reservoir cap exposure are provided.
Inventors: |
Sheppard, Norman F. JR.;
(Bedford, MA) ; Feakes, Christina M.; (Brighton,
MA) |
Correspondence
Address: |
SUTHERLAND ASBILL & BRENNAN LLP
999 PEACHTREE STREET, N.E.
ATLANTA
GA
30309
US
|
Family ID: |
23133541 |
Appl. No.: |
10/158811 |
Filed: |
May 30, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60294462 |
May 30, 2001 |
|
|
|
Current U.S.
Class: |
427/248.1 ;
118/665; 118/693 |
Current CPC
Class: |
A61K 9/0009 20130101;
Y10T 29/49155 20150115; A61K 9/0097 20130101; Y10T 29/49146
20150115 |
Class at
Publication: |
427/248.1 ;
118/665; 118/693 |
International
Class: |
C23C 016/00 |
Claims
We claim:
1. A microchip device for the controlled release or exposure of
molecules or secondary devices comprising: a substrate having a
plurality of reservoirs; reservoir contents comprising molecules, a
secondary device, or both, located in the reservoirs; reservoir
caps covering the reservoirs contents to isolate said contents from
one or more environmental components outside the reservoirs,
wherein the reservoir caps can be selectively disintegrated or
permeabilized to expose the reservoir contents within selected
reservoirs to said one or more environmental components; and a
conformal coating over the outer surface of at least a portion of
the substrate other than the reservoir caps.
2. The microchip device of claim 1, wherein the conformal coating
comprises a vapor depositable polymeric material.
3. The microchip device of claim 1, wherein the conformal coating
comprises a poly(para-xylylene).
4. The microchip device of claim 3, wherein the conformal coating
comprises Parylene C, Parylene N, Parylene D, or a combination
thereof.
5. The microchip device of claim 1, wherein the conformal coating
is selected from the group consisting of acrylics, polyurethanes,
silicones, and combinations thereof.
6. The microchip device of claim 1, wherein the conformal coating
has a thickness between 0.1 and 50 microns.
7. The microchip device of claim 6, wherein the conformal coating
has a thickness of about 10 microns.
8. The microchip device of claim 1, wherein the reservoir contents
comprise a drug.
9. The microchip device of claim 8, wherein the drug is selected
from the group consisting of analgesics, steroids, cytokines,
psychotropic agents, chemotherapeutic agents, hormones,
anesthetics, vaccines, metabolites, sugars, immunomodulators,
antioxidants, ion channel regulators, and antibiotics.
10. The microchip device of claim 1, wherein the reservoir contents
comprises molecules selected from the group consisting of proteins,
nucleic acids, polysaccharides, and cells.
11. The microchip device of claim 1, wherein the reservoir contents
comprises a secondary device.
12. The microchip device of claim 11, wherein the secondary device
comprises a sensor or sensor component.
13. The microchip device of claim 1, further comprising a means for
disintegrating or permeabilizing the barrier layer.
14. The microchip device of claim 13, further comprising control
circuitry to control said means for disintegrating or
permeabilizing.
15. The microchip device of claim 14, wherein the control circuitry
comprises electrical connections insulated by the conformal
coating.
16. The microchip device of claim 14, further comprising a power
source.
17. The microchip device of claim 1, wherein reservoir cap
comprises a metal membrane.
18. The microchip device of claim 1, wherein the conformal coating
covers all exterior surfaces of the device other than the reservoir
caps.
19. The microchip device of claim 1, wherein the conformal coating
is a laminate structure comprising two layers of parylene and a
layer of a metal positioned therebetween.
20. The microchip device of claim 1, wherein the substrate has a
front side and a back side, the back side comprising a plurality of
reservoir openings distal the reservoir caps on the front side, and
the openings are sealed, at least in part, with a barrier layer
comprising a conformal coating material.
21. The microchip device of claim 20, wherein the openings are
further sealed with a mechanical or chemical sealing system secured
over the barrier layer.
22. The microchip device of claim 20, wherein the barrier layer is
a laminate structure comprising two layers of a poly(para-xylylene)
and a layer of a metal positioned therebetween.
23. A method for sealing reservoirs containing molecules or devices
in a microchip device, the method comprising: providing a substrate
having a plurality of reservoirs, a front side, and a back side,
the back side comprising a plurality of reservoir openings distal
reservoir caps on the front side and in need of sealing; loading
reservoir contents comprising molecules, a secondary device, or
both, into the reservoirs; and applying a conformal coating barrier
layer onto the reservoir contents over at least the reservoir
openings to seal the reservoir openings.
24. The method of claim 23, wherein the conformal coating barrier
layer comprises parylene.
25. The method of claim 23, wherein the conformal coating barrier
layer is applied by vapor deposition.
26. The method of claim 23, further comprising securing a
mechanical or chemical sealing system over the conformal coating
barrier layer.
27. A method of applying a conformal coating to a microchip device
comprising: vapor depositing a conformal coating material onto a
microchip device which comprises a substrate having a front side, a
back side, and at least two reservoirs containing molecules or
devices for selective release or exposure, and reservoir caps
positioned on the front side of the substrate on each reservoir
over the molecules or devices, wherein release or exposure of the
molecules or devices from the reservoir is controlled by diffusion
through or disintegration of the reservoir cap; and providing that
the conformal coating does not coat or is removed from the
reservoir caps.
28. The method of claim 27, wherein the conformal coating material
comprises parylene.
29. The method of claim 27, wherein the reservoir caps are masked
with a masking material before the vapor depositing step.
30. The method of claim 27, wherein any coating material deposited
onto the surface of the reservoir caps is subsequently removed.
31. The method of claim 30, wherein the removal is by chemical or
plasma etching or by laser.
32. The microchip device of claim 13, wherein the means comprises
the application of an effective amount of thermal energy.
33. The microchip device of claim 13, wherein the means comprises
an electrochemical reaction.
34. The method of claim 23, wherein the conformal coating barrier
layer is a laminate structure comprising two layers of a conformal
coating material and a layer of a metal positioned therebetween.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] Priority is claimed under 35 U.S.C. .sctn.119 to U.S.
provisional application Serial No. 60/294,462, filed May 30,
2001.
BACKGROUND OF THE INVENTION
[0002] This invention is generally in the field of implantable
miniaturized devices that provide controlled delivery or exposure
of molecules or smaller devices. More specifically, the invention
relates to implantable microchip devices.
[0003] When an implanted medical device such as a pacemaker is
placed in the body, one needs to consider both the impact of the
body on the device and the impact of the device on the body. The
environment is electrically conductive and relatively corrosive,
which can compromise the integrity and performance of the device
electrically or mechanically. The presence of a foreign object in
the body triggers the body's defense mechanisms, which can impair
the functioning of the body and/or the device. One commonly used
method to enhance the body's acceptance of the implanted device is
coat the device with a biocompatible coating material.
[0004] Pinhole-free, conformal coatings are designed to seal
devices from liquids and gases, while protecting and electrically
insulating the device. Such coatings are typically used to conform
to the surface contours of an assembled printed circuit board and
electronic components. They protect the circuitry from the
environment, prevent damage, provide mechanical strength, and
increase dielectric strength between components. Examples of
conformal coatings include silicone, urethane, acrylic, and epoxy.
Typical methods for depositing these coatings include dipping,
spraying, spin coating, and ultraviolet (UV) curing. U.S. Pat. No.
5,510,138 discloses a method of applying such coatings using hot
melt dispensing equipment. Although these conformal coatings and
processes are adequate for coating electronics and circuits, they
may be inappropriate for microchip chemical delivery devices, such
as described in U.S. Pat. Nos. 5,797,898 and 6,123,861 to Santini,
Jr. et al. and in Nature, 397:335-38 (1999) and Angewandte Chemie,
39:2396-407 (2000). Most of the typical coatings require a high
temperature or UV cure. Some are also solvent-based coatings, which
could adversely react with the reservoir contents (e.g., drug
molecules or a device) in the microchip device. These types of
coatings also may be unacceptable due to trapped air bubbles and
uneven coating.
[0005] Another coating material is parylene, which is used in
numerous medical applications. Parylene is the common name of a
family of vapor-deposited conformal coatings based on para-xylylene
and its derivatives. U.S. Pat. Nos. 5,393,533 and 5,288,504
disclose the use of parylene in controlled release applications
involving the encapsulation of drugs and cells for therapeutic
applications. Catheters and other molded surgical devices can be
parylene coated to protect the device against the corrosive effects
of biofluids and can also aid in the release of these devices from
the fabrication molds. U.S. Pat. No. 5,425,710 discloses using
parylene coating to coat a sleeve of a dilation catheter balloon to
protect it during insertion. As disclosed in U.S. Pat. No.
5,824,049, stents and prostheses can be parylene coated to protect
them and allow cells to proliferate on them. Parylene provides
corrosion resistance and electrical insulation on sensors implanted
in the body without altering the device operation. U.S. Pat. No.
5,067,491 describes a blood pressure monitoring device coated in
parylene to protect the sensor from the effects of the blood, ions,
and water. Both the lumen and the outside of needles and probes can
be coated with parylene to create a smooth surface. These needles
may be used to make microelectrodes, as disclosed in U.S. Pat. No.
5,524,338. Implantable pacemakers and defibrillators can be sealed
with parylene to protect and electrically insulate the devices.
[0006] One difficulty in using parylene to coat a microchip device
would be that the reservoir caps over each reservoir of the
completed microchip device must not be coated, in order for the
device to operate. Therefore, the coating process would need to be
followed by a selective removal process. Other types of implantable
devices have a similar need to remove parylene from a portion of
the device. For example, U.S. Pat. No. 5,925,069 (Sulzer
Intermedics) discloses using a pulsed excimer laser to remove
parylene coating from the surface of an implantable cardiac pulse
generator to expose a defined region of the case to serve as an
electrode. A UV-resistant mask or stencil between the device and
the laser beam is used to create windows or openings in the
parylene coating. This patent also discloses the use of plasma
etching to remove parylene in patterns having defined shapes. In
this process, the organic parylene reacts with the ionized oxygen
plasma to form carbon dioxide gas and water vapor, which are
removed by vacuum. A mask can create patterns of various shapes in
the parylene by protecting certain areas from etching.
[0007] U.S. Pat. No. 5,562,715 discloses a silicone rubber or
parylene coated pacemaker with detachable tabs that remove a
portion of the coating and expose the electrodes. Windows in the
parylene coating are patterned using a process that includes
masking select surface areas of the device with tape, coating the
entire surface of the device (masked and unmasked) with parylene,
and then removing the tape to expose the select surface areas.
[0008] U.S. Pat. No. 4,734,300 discloses a process for the
selective removal of parylene by contacting the areas of parylene
to be removed with a chemical substance, such as tetrahydrofuran,
to loosen the parylene coating so that it can be physically
removed. A knife is used to score the parylene coating.
[0009] Such masking techniques may not be readily adaptable for
masking individual tiny reservoir caps, which may, for example, be
positioned in a closely packed array in a microchip device. For
example, it may be difficult to create well-defined boundaries
between coated and uncoated areas in very small microchip
devices.
[0010] In one process of assembling microchip chemical delivery
devices, it is necessary to seal the reservoir openings (distal the
reservoir caps) after filling the reservoirs with the drug
molecules or other reservoir contents. It would be advantageous to
be able to seal the reservoir openings with a material that is
compatible with the reservoir contents.
[0011] It would be desirable to provide microchip devices having a
coating which enhances biocompatibility of the device and protects
and insulates the device electronics, and which is compatible with
the reservoir contents. It also would be desirable to provide a
method of conformally coating a microchip device to seal the drug
reservoirs, to electrically insulate the electrical connections,
and to provide a biocompatible outer surface. It also would be
desirable to provide microfabrication techniques for use in
patterning a conformal coating on a microchip device so as to
selectively pattern well-defined microscopic openings in the
coating which correspond to the reservoir caps of the microchip
device.
SUMMARY OF THE INVENTION
[0012] Microchip devices are provided with a conformal coating to
give an inert and biocompatible surface for implantation of the
microchip device, mitigating adverse responses by the body
following implantation. In one embodiment, the microchip device for
the controlled release or exposure of molecules or devices
comprises: (1) a substrate having a plurality of reservoirs; (2)
reservoir contents comprising molecules, a secondary device, or
both, located in the reservoirs; (3) reservoir caps covering the
reservoirs contents to isolate the reservoir contents from one or
more environmental components outside the reservoirs; and (4) a
conformal coating over the outer surface of at least a portion of
the substrate other than the reservoir caps. The reservoir caps can
be selectively disintegrated or permeabilized to expose the
reservoir contents within selected reservoirs to the one or more
environmental components. The conformal coating preferably
comprises a vapor depositable polymeric material, such as parylene,
which is biocompatible. In other embodiments, the biocompatible
conformal coating includes acrylics, polyurethanes, silicones, or
combinations thereof. The conformal coating has a thickness between
0.1 and 50 microns, preferably 10 microns. The conformal coating
preferably covers all exterior surfaces of the device other than
the reservoir caps. In one embodiment, the conformal coating is a
laminate structure comprising two layers of parylene and a layer of
a metal positioned therebetween.
[0013] In one embodiment, the reservoir contents comprise at least
one therapeutic, prophylactic, or diagnostic agent. In another
embodiment, the reservoir contents comprise a biosensor. The
microchip device can include control circuitry to control the
disintegration or permeabilization. It may further include a power
source.
[0014] In another aspect, the microchip device includes a substrate
having a front side and a back side, the back side comprising a
plurality of reservoir openings distal the reservoir caps on the
front side. The openings are sealed, at least in part, with a
barrier layer comprising a conformal coating material. The openings
can be further sealed with a mechanical or chemical sealing system
secured over the barrier layer. The barrier layer also can be a
laminate structure comprising two layers of parylene and a layer of
a metal positioned therebetween.
[0015] Methods are provided for sealing reservoirs containing
molecules or devices in a microchip device. The method can include
(1) providing a substrate having a plurality of reservoirs, a front
side, and a back side, the back side comprising a plurality of
reservoir openings distal reservoir caps on the front side and in
need of sealing; (2) loading reservoir contents comprising
molecules, a secondary device, or both, into the reservoirs; and
(3) applying a conformal coating barrier layer onto the reservoir
contents over at least the reservoir openings to seal the reservoir
openings. The conformal coating barrier layer can be applied by
vapor deposition.
[0016] Methods are also provided for applying a conformal coating
to a microchip device. The method can include (1) vapor depositing
a conformal coating material onto a microchip device which
comprises a substrate having a front side, a back side, and at
least two reservoirs containing molecules or devices for selective
release or exposure, and reservoir caps positioned on the front
side of the substrate on each reservoir over the molecules or
devices, wherein release or exposure of the molecules or devices
from the reservoir is controlled by diffusion through or
disintegration of the reservoir cap; and (2) providing that the
conformal coating does not coat or is removed from the reservoir
caps. In one embodiment, the reservoir caps are masked with a
masking material before the vapor depositing step. In another
embodiment, any coating material deposited onto the surface of the
reservoir caps is subsequently removed, such as by chemical or
plasma etching or by excimer laser.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 depicts the chemical structures of Parylene C,
Parylene N, and Parylene D.
[0018] FIG. 2 is a process flow diagram illustrating one embodiment
of a parylene conformal coating process.
[0019] FIG. 3 illustrates, in cross-sectional views, one embodiment
of a process for fabricated a conformally coated microchip device,
wherein tape masking is used to pattern a parylene conformal
coating.
[0020] FIG. 4 illustrates, in cross-sectional views, one embodiment
of a process for fabricated a conformally coated microchip device,
wherein an excimer laser is used to remove the coating over the
reservoir caps.
[0021] FIG. 5 illustrates, in cross-sectional views, one embodiment
of a process for fabricated a conformally coated microchip device,
wherein the conformal coating includes a metal layer interposed
between two layers of parylene.
DETAILED DESCRIPTION OF THE INVENTION
[0022] Microchip devices having a conformal coating are provided
that store and protect molecules and smaller devices from the
environment for a period of time until controlled release or
exposure of the molecules or smaller devices to the environment is
desired. The microchip device includes (1) a substrate having a
plurality of reservoirs; (2) reservoir contents comprising
molecules, a secondary device, or both, located in the reservoirs;
(3) reservoir caps covering the reservoirs contents to isolate said
contents from one or more environmental components outside the
reservoirs, wherein the reservoir caps can be selectively
disintegrated or permeabilized to expose the reservoir contents
within selected reservoirs to the one or more environmental
components; and (4) a conformal coating over the outer surface of
at least a portion of the substrate other than the reservoir caps.
As used herein, the term "one or more environmental components"
simply refers to constituents of the environment external the
reservoirs, including, but not limited to, biological tissues and
fluids at the site of implantation, air, fluids and particulates
present during storage or in vitro use of the microchip
devices.
[0023] The conformal coating preferably provides an inert and
biocompatible surface for implantation of the microchip device,
mitigating adverse responses by the body following implantation.
The coating process desirably is one that avoids the need for
solvents, heat, or chemical techniques that could degrade or damage
the drug and/or device. For example, parylene can be deposited from
a vapor preferably at room temperature and at a vacuum of
approximately 0.1 torr. This is particularly advantageous for
temperature sensitive drug molecules, which otherwise may be
degraded by high temperature sealing or coating processes. The
coating methods provide a means for containing and sealing a drug
or other material in a microchip device, electrically insulating
the electrical connections to the microchip, and at the same time
provide an inert biocompatible coating suitable for implantation in
the human body.
[0024] The microchip devices include a substrate having a plurality
of reservoirs that contain the molecules or devices (i.e. the
reservoir contents). The reservoirs can be individually filled and
addressed, enabling the time and rate of release of multiple
chemicals to be controlled. The reservoirs are closed at a first
surface of the substrate by a reservoir cap or other membrane.
Release or exposure of reservoir contents is from this first
surface. The reservoirs also are closed at a second surface of the
substrate distal the first surface. The reservoir opening at the
second surface is sealed following filling of the reservoir with
the reservoir contents. The conformal coating is applied either
following or as part of the sealing process.
[0025] As used herein, a "microchip" is a miniaturized device
fabricated using methods described in U.S. Pat. Nos. 5,797,898 and
6,123,861, to Santini, Jr. et al., as well as other methods
commonly applied to the manufacture of integrated circuits and MEMS
(MicroElectroMechanical Systems) such as ultraviolet (UV)
photolithography, reactive ion etching, and electron beam
evaporation, as described, for example, by Wolf & Tauber,
Silicon Processing for the VLSI Era, Volume 1-Process Technology
(Lattice Press, Sunset Beach, Calif., 1986); and Jaeger,
Introduction to Microelectronic Fabrication, Volume V in The
Modular Series on Solid State Devices (Addison-Wesley, Reading,
Mass., 1988), as well as MEMS methods that are not standard in
making computer microchips, including those described, for example,
in PCT WO 01/41736 and Madou, Fundamentals of Microfabrication (CRC
Press, 1997), and other micromolding and micromachining and polymer
forming techniques known in the art.
[0026] I. Device Components and Materials
[0027] The microchip devices include a substrate having a plurality
of reservoirs, which contain the molecules or devices (i.e. the
reservoir contents). The substrate, reservoirs, release system,
reservoir caps, control circuitry and power source are
substantially as described in U.S. Pat. Nos. 5,797,898 and
6,123,861, as well as PCT WO 02/30401, WO 02/30264, WO 01/91902, WO
01/64344, WO 01/41736, WO 01/35928, and WO 01/12157. A conformal
coating is provided on select surfaces of the microchip device.
[0028] The Substrate
[0029] The substrate contains the reservoirs and serves as the
support for the microchip. Any material which can serve as a
support, which is suitable for etching or machining or which can be
cast or molded, and which is impermeable to the contents of the
reservoir and to the surrounding environment (e.g., water, blood,
electrolytes, other solutions, or air) may be used as a substrate.
Examples of suitable substrate materials include ceramics, glasses,
certain metals, semiconductors, and degradable and non-degradable
polymers. The substrate can be formed of only one material or can
be a composite or multi-laminate material.
[0030] Conformal Coating
[0031] The material forming the conformal coating can be
essentially any material or combination of materials that provide
one or more, and preferably several, of the desired functions:
strength, stability, biocompatibility, electrical insulation,
moisture barrier properties, and processability (e.g., suitable
parameters for application onto the microchip device). The material
and application process desirably provides a uniform, bubble-free,
pinhole-free coating. In a preferred embodiment, the conformal
coating is provided over the entire surface of the microchip device
with the exception of the reservoir caps.
[0032] The term "conformal" is used herein as known in the art, and
refers to a coating designed to conform to the surface of the
article being coating.
[0033] Parylene is the preferred conformal coating material.
Parylene is the generic name for a family of poly(para-xylylene)
polymers. There are a number of types of parylene, including
Parylene N, Parylene C, and Parylene D. FIG. 1 shows the chemical
structures for each of these three parylenes. They differ in the
atomic substituents on the benzene ring of the xylylene molecule,
which imparts different properties to the films, such as barrier
protection, thermal stability, and lubricity. As used herein, the
term "parylene" refers to any poly(para-xylylene) polymer or
mixture thereof, unless a particular one is expressly indicated.
Parylene is commercially available from such companies as Specialty
Coating Systems (Indianapolis, Ind. USA) and Paratronix (Attleboro,
Mass. USA).
[0034] Parylene is an effective coating as a moisture barrier.
Parylene N absorbs 0.01% of water over 24 hours for a 0.019 inch
(480 .mu.m) thick coating, and Parylene C absorbs 0.06% of water
over 24 hours for a 0.029 inch (740 .mu.m) thick coating. Parylene
N and Parylene C have also been tested and used in FDA approved
implantable medical devices. These parylenes have been certified to
comply with USP biological testing requirements for Class VI
Plastics, which include Acute Systemic Toxicity,
Irritation/Intracutaneous Reactivity, and Implantation.
[0035] Parylene is also an excellent electrical insulator. The
short time dielectric strength of Parylene N is 7000 volts/mil
(2.8.times.10.sup.8 V/m), Parylene C 6800 volts/mil
(2.7.times.10.sup.8 V/m), and Parylene D 5500 volts/mil
(2.2.times.10.sup.8 V/m), at 1 mil (25.times.10.sup.6 m).
[0036] The thickness of the parylene coating typically is between
0.1 microns and 50 microns or more. The particular thickness
preferred depends upon the particular application and reservoir
contents. As a general rule, the thicker the coating, the better
the barrier properties of the coating. For example, the resistance
to moisture transmission through the coating increases with
increasing coating thickness. However, if one needs to define
windows (i.e. open, uncoated areas) in the coating, for example to
expose the reservoir caps, then that is more easily accomplished
with a thinner coating. For example, making an accurate, 50 .mu.m
wide hole in a 10 .mu.m thick film is easier than making the same
hole in a 50 .mu.m thick film. If the coating is too thin, however,
pinholes may be formed in the film, unless the coating process is
conducted in a cleanroom. In a preferred embodiment, the parylene
coating thickness is about 10 .mu.m.
[0037] Representative examples of other materials that may be
suitable conformal coating materials include acrylics,
polyurethanes, and silicones. Other vapor depositable,
biocompatible, polymeric materials, including plasma-deposited
polymer films, as well as materials having chemistries similar to
that of parylene also can be used.
[0038] Conformal Coating Material as Barrier Layer
[0039] In an alternative embodiment, a vapor depositable conformal
coating material, preferably parylene, is included as a barrier
layer interposed between the reservoir contents and any other
sealing material (to seal the opening used to fill the
reservoirs--not to seal the reservoir cap side). In this
embodiment, the conformal coating material can, but need not, coat
the entire microchip device or device package. That is, the vapor
depositable barrier layer material may coat the entire device or a
portion thereof which includes the reservoir openings distal the
reservoir caps.
[0040] The selected barrier layer desirably is compatible with the
reservoir contents and generally would have little or no mixing
with drug or other molecules in the reservoir. The coating material
would be applied to form a solid or gel barrier layer. Following
deposition of the barrier layer, any type of mechanical or chemical
sealing system can be applied over or onto the barrier layer.
Representative examples of mechanical sealing systems include the
use of backing plates, such as described in PCT WO 01/91902. When a
chemical sealing system is employed (e.g., epoxy), little or no
mixing should occur at the interface of the barrier layer and
chemical sealing system prior to cross-linking the sealing
system.
[0041] Molecules and Secondary Devices (Reservoir Contents)
[0042] The reservoirs contain molecules, secondary devices, or
combinations thereof, that need to be protected from surrounding
environmental components until their release or exposure is
desired. Proper functioning of certain reservoir contents, such as
a catalyst or sensor, generally does not require their release from
the reservoir; rather their intended function, e.g., catalysis or
sensing, occurs upon exposure of the reservoir contents to the
environment outside of the reservoir after opening of the reservoir
cap. Thus, the catalyst molecules or sensing component can be
released or can remain immobilized within the open reservoir.
[0043] Molecules
[0044] The reservoir contents can include essentially any natural
or synthetic, organic or inorganic molecule or mixture thereof, for
release (i.e. delivery) or retained and exposed. The molecules
(i.e. chemicals) may be in pure solid, liquid, or gel form, or
mixed with other materials that affect the release rate and/or
time. Chemicals may be in the form of solid mixtures including, but
not limited to, amorphous and crystalline mixed powders, monolithic
solid mixtures, lyophilized powders, and solid interpenetrating
networks; in the form of liquid mixtures including, but not limited
to, solutions, emulsions, colloidal suspensions, and slurries; and
in the form of gel mixtures including, but not limited to,
hydrogels.
[0045] For in vivo applications, the chemical preferably is a
therapeutic, prophylactic, or diagnostic agent. In one embodiment,
the microchip device is used to deliver drugs systemically to a
patient in need thereof. In another embodiment, the construction
and placement of the microchip in a patient enables the local or
regional release of drugs that may be too potent for systemic
delivery of an effective dose. As used herein, "drugs" include any
therapeutic, prophylactic or diagnostic agent, including organic or
inorganic molecules, proteins, nucleic acids, polysaccharides and
synthetic organic molecules, having a bioactive effect.
Representative examples include analgesics, steroids, cytokines,
psychotropic agents, chemotherapeutic agents, hormones,
anesthetics, vaccines, metabolites, sugars, immunomodulators,
antioxidants, ion channel regulators, and antibiotics. An example
of a diagnostic agent is an imaging agent such as a contrast agent.
The drugs can be in the form of a single drug or drug mixtures and
can include pharmaceutically acceptable carriers.
[0046] In another embodiment, molecules are released in vitro in
any system where the controlled release of a small (milligram to
nanogram) amount of one or more molecules is required, for example,
in the fields of analytic chemistry or medical diagnostics.
Molecules can be effective as pH buffering agents, diagnostic
reagents, and reagents in complex reactions such as the polymerase
chain reaction or other nucleic acid amplification procedures.
[0047] In another embodiment, the molecules to be released are
perfumes, fragrances, dyes, coloring agents, sweeteners, or a
variety of other compounds, which for example, may be useful to
release as a function of temperature change.
[0048] In other embodiments, the reservoirs contain immobilized
molecules. Examples include any chemical species which can be
involved in a reaction, including, but not limited to, reagents;
catalysts, including enzymes, metals, and zeolites; proteins;
nucleic acids; polysaccharides; polymers; cells, as well as organic
or inorganic molecules, including diagnostic agents.
[0049] Formulations of molecules to be released also may contain
stabilizers and anti-oxidants to preserver the integrity of the
drug or other molecules.
[0050] Secondary Devices
[0051] As used herein, unless explicitly indicated otherwise, the
term "secondary device" includes, but is not limited to, any device
and component thereof which can be located in or designed to
operably communicate with one or more reservoirs in a microchip
device. In a preferred embodiment, the secondary device is a sensor
or sensing component. As used herein, a "sensing component"
includes, but is not limited to, a component utilized in measuring
or analyzing the presence, absence, or change in a chemical or
ionic species, energy, or one or more physical properties (e.g.,
pH, pressure) at a site. Types of sensors include biosensors,
chemical sensors, physical sensors, or optical sensors. Secondary
devices are further described in PCT WO 01/64344.
[0052] Examples of sensing components include components utilized
in measuring or analyzing the presence, absence, or change in a
drug, chemical, or ionic species, energy (or light), or one or more
physical properties (e.g., pH, pressure) at a site. In a preferred
embodiment, the microchip device is implantable in a patient (e.g.,
a human or other mammal) and includes sensors for monitoring the
levels of glucose or urea in blood and other body fluids.
[0053] There are several different options for receiving and
analyzing data obtained with devices located in the microchip
devices. Typically, the operation of the microchip system will be
controlled by an on-board (i.e. within the package) microprocessor.
The output signal from the device, after conditioning by suitable
circuitry if needed, will be acquired by the microprocessor. After
analysis and processing, the output signal can be stored in a
writeable computer memory chip, and/or can be sent (e.g.,
wirelessly) to a remote location away from the microchip. Power can
be supplied to the microchip system locally by a microbattery or
remotely by wireless transmission.
[0054] Reservoir Caps
[0055] As used herein, the "reservoir cap" includes a membrane, a
reservoir cap, a plug, a thick or thin solid or semi-solid film, a
two-phase interface (i.e. solid-liquid, liquid-liquid, or
liquid-gas), or any other physical or chemical structure suitable
for separating the contents of a reservoir from the environment
outside of the reservoir. It generally is self-supporting across
the reservoir opening. Selectively removing the reservoir cap or
making it permeable will then "expose" the contents of the
reservoir to the environment (or selected components thereof)
surrounding the reservoir. In preferred embodiments, the barrier
layer can be selectively disintegrated. As used herein, the term
"disintegrate" is used broadly to include without limitation
degrading, dissolving, rupturing, fracturing or some other form of
mechanical failure, as well as a loss of structural integrity due
to a chemical reaction or phase change, e.g., melting, in response
to a change in temperature, unless a specific one of these
mechanisms is indicated.
[0056] In passive devices, the reservoir cap is formed from a
material or mixture of materials that degrade, dissolve, or
disintegrate over time, or that do not degrade, dissolve, or
disintegrate, but are permeable or become permeable to molecules or
energy. Representative examples of reservoir cap materials include
polymeric materials, and non-polymeric materials such as porous
forms of metals, semiconductors, and ceramics. Passive
semiconductor barrier layer materials include nanoporous or
microporous silicon membranes.
[0057] In active devices, the reservoir cap includes any material
that can be disintegrated or permeabilized in response to an
applied stimulus (e.g., electric field or current, magnetic field,
change in pH, or by thermal, chemical, electrochemical, or
mechanical means). In a preferred embodiment, the reservoir cap is
a thin metal membrane and is impermeable to the surrounding
environment (e.g., body fluids or another chloride containing
solution). Based on the type of metal and the surrounding
environment, a particular electric potential is applied to the
metal reservoir cap, which is then oxidized and disintegrated by an
electrochemical reaction, to expose the contents of the reservoir
to the surrounding environment. Examples of suitable reservoir cap
materials include gold, silver, copper, and zinc. Any combination
of passive or active barrier layers can be present in a single
microchip device.
[0058] Device Packaging, Control Circuitry and Power Source
[0059] Active devices require actuation, which typically is done
under the control of a microprocessor. The microprocessor is
programmed to initiate the disintegration or permeabilization of
the reservoir cap in response at a pre-selected time or in response
to one or more of signals or measured parameters, including receipt
of a signal from another device (for example by remote control or
wireless methods) or detection of a particular condition using a
sensor such as a biosensor.
[0060] Microelectronic device packages are typically made of an
insulating or dielectric material such as aluminum oxide or silicon
nitride. Low cost packages can also be made of plastics. Their
purpose is to allow all components of the device to be placed in
close proximity and to facilitate the interconnection of components
to power sources and to each other, while protecting the
electronics from the environment.
[0061] The control circuitry includes a microprocessor, a timer, a
demultiplexer, and an input source (for example, a memory source, a
signal receiver, or a biosensor), and a power source. The timer and
demultiplexer circuitry can be designed and incorporated directly
onto the surface of the microchip during electrode fabrication. The
criteria for selection of a microprocessor are small size, low
power requirement, and the ability to translate the output from
memory sources, signal receivers, or biosensors into an address for
the direction of power through the demultiplexer to a specific
reservoir on the microchip device (see, e.g., Ji, et al., IEEE J.
Solid-State Circuits 27:433-43 (1992)). Selection of a source of
input to the microprocessor such as memory sources, signal
receivers, or biosensors depends on the microchip device's
particular application and whether device operation is
preprogrammed, controlled by remote means, or controlled by
feedback from its environment (i.e. biofeedback).
[0062] The criteria for selection of a power source are small size,
sufficient power capacity, ability to be integrated with the
control circuitry, the ability to be recharged, and the length of
time before recharging is necessary. Batteries can be separately
manufactured (i.e. off-the-shelf) or can be integrated with the
microchip itself. Several lithium-based, rechargeable
microbatteries are described in Jones & Akridge, "Development
and performance of a rechargeable thin-film solid-state
microbattery", J. Power Sources, 54:63-67 (1995); and Bates et al.,
"New amorphous thin-film lithium electrolyte and rechargeable
microbattery", IEEE 35.sup.th International Power Sources
Symposium, pp. 337-39 (1992). These batteries are typically only
ten microns thick and occupy 1 cm.sup.2 of area. One or more of
these batteries can be incorporated directly onto the microchip
device. Binyamin, et al., J. Electrochem. Soc., 147:2780-83 (2000)
describes work directed toward development of biofuel cells, which
if developed, may provide a low power source suitable for the
operation of the microchip devices described herein, as well as
other microelectronic devices, in vivo.
[0063] A microprocessor is used in conjunction with a source of
memory such as programmable read only memory (PROM), a timer, a
demultiplexer, and a power source such as a microbattery, as
described, for example, by Jones et al. (1995) and Bates et al.
(1992), or a biofuel cell, as described by Binyamin, et al. (2000).
A programmed sequence of events including the time a reservoir is
to be opened and the location or address of the reservoir is stored
into the PROM by the user. When the time for exposure or release
has been reached as indicated by the timer, the microprocessor
sends a signal corresponding to the address (location) of a
particular reservoir to the demultiplexer. The demultiplexer routes
an input, such as an electric potential or current, to the
reservoir addressed by the microprocessor.
[0064] II. Methods of Making the Microchip Devices
[0065] The assembly of a complete microchip drug delivery device
involves a number of packaging steps which may include (1)
attachment of electrical leads to the microchip, (2) filling of the
reservoirs with a chemical molecules or secondary devices for
release or exposure, (3) sealing the reservoirs, (4) integration
with electronic components and power sources, and (5) placing all
microchips and components within a single enclosure or "package."
For in vivo applications, this entire "package" must also be
biocompatible. One possible assembly sequence might include filling
the microchip, filling the reservoirs, attaching the electrical
connections and leads, and sealing the entire package with a
conformal coating.
[0066] Fabrication of the Substrates with Reservoirs
[0067] The microchip devices can be made using the methods
described below, alone or in combination with known methods, such
the microfabrication techniques described in U.S. Pat. Nos.
5,797,898 and 6,123,861, to Santini, et al. Other methods are
described in PCT WO 01/41736. For example, the substrate can be
formed from polymer, ceramic, or metal, e.g., by compression
molding powders or slurries of polymer, ceramic, metal, or
combinations thereof. Other forming methods useful with these
materials include injection molding, thermoforming, casting,
machining, and other methods known to those skilled in the art.
Substrates formed using these methods can be formed (e.g., molded)
to have the reservoirs or the reservoirs can be added in subsequent
steps, such as by etching.
[0068] Fabrication of Reservoir Caps
[0069] In the fabrication of passive microchip devices, the
reservoir cap material preferably is injected with a micro-syringe,
printed with an inkjet printer cartridge, or spin coated into a
reservoir having the thin membrane of insulating mask material
still present over the small opening of the reservoir. If injection
or inkjet printing methods are used, reservoir cap formation is
complete after the material is injected or printed into the
reservoir and does not require further processing. If spin coating
is used, the reservoir cap material is planarized by multiple spin
coatings. The surface of the film is then etched by a plasma, ion
beam, or chemical etchant until the desired reservoir cap thickness
is obtained. After deposition of the reservoir cap material, and
possibly after reservoir filling, the insulating mask material is
removed, typically via dry or wet etching techniques. It is
understood that each reservoir also can be capped individually by
capillary action, by pulling or pushing the material into the
reservoir using a vacuum or other pressure gradient, by melting the
material into the reservoir, by centrifugation and related
processes, by manually packing solids into the reservoir, or by any
combination of these or similar reservoir filling techniques.
[0070] In active devices, the reservoir cap and related circuitry
can be deposited, patterned, and etched using microelectronic and
MEMS fabrication methods well known to those skilled in the art,
reviewed, for example, by Wolf et al. (1986), Jaeger (1988), and
Madou, Fundamentals of Microfabrication (CRC Press, 1997). The
reservoir cap and associated circuitry also can be formed on the
surface of microchip devices using microcontact printing and soft
lithography methods, as described, for example, in Yan, et al., J.
Amer. Chem. Soc., 120:6179-80 (1998); Xia, et al., Adv. Mater.,
8(12):1015-17 (1996); Gorman, et al., Chem. Mater., 7:52-59 (1995);
Xia, et al., Annu. Rev. Mater. Sci., 28:153-84 (1998); and Xia, et
al., Angew. Chem. Int. Ed., 37:550-75 (1998). In a preferred
embodiment, the barrier layer is defined using a lift-off
technique. Briefly, photoresist is patterned in the form of
electrodes on the surface of the substrate having the reservoirs
covered by the thin membrane of insulating or dielectric material.
The photoresist is developed such that the area directly over the
covered opening of the reservoir is left uncovered by photoresist
and is in the shape of an anode. A thin film of conductive material
capable of dissolving into solution or forming soluble ions or
oxidation compounds upon the application of an electric potential
is deposited over the entire surface using deposition techniques
such as chemical vapor deposition, electron or ion beam
evaporation, sputtering, spin coating, and other techniques known
in the art. Exemplary materials include metals such as copper,
gold, silver, and zinc and some polymers, as disclosed by Kwon et
al. (1991) and Bae et al. (1994). After film deposition, the
photoresist is stripped from the substrate. This removes the
deposited film, except in those areas not covered by photoresist,
which leaves conducting material on the surface of the substrate in
the form of electrodes. The anode serves as the active reservoir
cap and the placement of the cathodes on the device is dependent
upon the device's application and method of electric potential
control. The electrodes are positioned in such a way that when a
suitable electric potential is applied between an anode and a
cathode, the unprotected (not covered by dielectric) portion of the
anode barrier layer oxidizes to form soluble compounds or ions that
disintegrate into solution, compromising the barrier separating the
reservoir contents from the surrounding environment.
[0071] Reservoir Filling
[0072] The chemicals and devices to be stored and protected within
the reservoirs are inserted into one of the openings of each
reservoir (e.g., the large opening of square pyramid-shaped
reservoirs). Chemicals can be inserted into the reservoir by
injection, inkjet printing, or spin coating. Devices or device
components can be fabricated inside or near each reservoir, or can
be fabricated away from the microchip and inserted into or placed
near a reservoir during microchip and packaging assembly. Each
reservoir can contain different chemicals, devices, or device
components. It is understood that each reservoir can be filled
individually by capillary action, by pulling or pushing the
material into the reservoir using a vacuum or other pressure
gradient, by melting the material into the reservoir, by
centrifugation and related processes, by manually packing solids
into the reservoir, or by any combination of these or similar
reservoir filling techniques. Each reservoir can also contain a
different device or device component. Such devices can be
fabricated directly in each reservoir. In one embodiment, thin
metal electrodes for use in a sensing application can be fabricated
onto the sidewalls of a pyramid-shaped reservoir using
photolithography and electron beam evaporation.
[0073] Device Packaging, Control Circuitry, and Power Source
[0074] The manufacture, size, and location of the power source,
microprocessor, PROM, timer, demultiplexer, and other components
are dependent upon the requirements of a particular application. In
a preferred embodiment, the memory, timer, microprocessor, and
demultiplexer circuitry is integrated directly onto the surface of
the microchip. The microbattery is attached to the other side of
the microchip and is connected to the device circuitry by vias or
thin wires. However, in some cases, it is possible to use separate,
prefabricated, component chips for memory, timing, processing, and
demultiplexing. In a preferred embodiment, these components are
attached to the back side of the microchip device with the battery.
In another preferred embodiment, the component chips and battery
are placed on the front of or next to the microchip device, for
example similar to how it is done in multi-chip modules (MCMs) and
hybrid circuit packages. The size and type of prefabricated chips
used depends on the overall dimensions of the microchip device and
the number of reservoirs, and the complexity of the control
required for the application.
[0075] Coating and Sealing the Microchip Devices
[0076] The openings through which the reservoirs of the devices are
filled generally must subsequently be sealed. This sealing can be
by mechanically or chemically securing a backplate over the
openings. Alternatively, the opening can be sealed by applying a
fluid material (e.g., an adhesive such as epoxy, a wax, or a
polymer) that plugs the opening and hardens to form a seal that is
impervious to the surrounding environment. Following this sealing
process, a separate conformal coating can be applied. In an
alternative embodiment, the conformal coating is used in place of a
separate sealing step, such that the conformal coating is used to
seal the reservoir openings and provide the biocompatible coating
surface over the entire microchip device package.
[0077] In one embodiment, after electrical connections have been
made in the circuitry (e.g., for providing the electrical potential
means for disintegrating each reservoir cap), the reservoirs are
ready to be filled with drug molecules. The conformal coating can
then be applied directly onto the substrate and filled reservoirs,
or alternatively, an intermediate coating, such as a wax layer, may
be deposited after drug filling and before parylene coating in
order to enhance reservoir sealing or eliminate trapped air
pockets. In another embodiment, the barrier properties of the
sealing layer can be improved by vapor depositing a layer of
parylene over the open ends of the filled reservoirs. A metal layer
is then sputtered or evaporated over the first parylene layer.
Finally, another layer of parylene is deposited over the metal
layer to give a biocompatible outer surface.
[0078] (a). Conformal Coating Process
[0079] Known conformal coating processes can be selected and used
based, at least in part, on the coating material and any process
limitations of the microchip device (e.g., temperature limitations
of the reservoir contents).
[0080] Depending on the conformal coating process, it may be
advantageous to chemically treat, or prime, the surfaces of the
microchip device so as to improve the adhesion of the conformal
coating. The family of materials known as silane adhesion promoters
may be used on the silicon surfaces of the microchip device, and
specific silanes, such as gamma-aminopropyltriethoxy silane, are
often used for glass and silicon dioxide surfaces. The adhesion
promoter may need to be applied before the reservoir contents are
loaded into the microchip to prevent the drug molecules or other
contents from being exposed to the silane. Substrates formed of
materials other than silicon can be primed with other known
adhesion promoters suitable for the particular substrate/conformal
coating material selected.
[0081] One embodiment of a parylene deposition system 10 is shown
in FIG. 2. To conformally coat the microchip devices (alone or with
a carrier and associated leads) 12 with parylene, the assembled
devices 12 are placed in a deposition chamber 14 of the parylene
deposition system at room temperature. The source of parylene, the
parylene dimer 16, is placed in a sublimation chamber (or
vaporizer) 18 at the opposite end of the deposition system. The
thickness of the parylene coating is determined by the volume of
the dimer placed in the chamber. The dimer is heated, for example
to about 175.degree. C., in the sublimation chamber to cause it to
sublimate. A pyrolysis tube 20 is located in fluid communication
between the deposition chamber and the sublimation chamber. The
deposition chamber 14 is held at a slight vacuum, for example with
vacuum pump 22, so the pressure difference between the chambers
moves the vaporized parylene dimer molecules through the pyrolysis
tube 20. Exemplary values could be 1 torr in the sublimation
chamber, 0.5 torr in the pyrolysis tube, and 0.1 torr in the
deposition chamber. In the pyrolysis tube 20, the parylene dimer is
then heated, for example to about 680.degree. C., to cause it to
cleave into two radical monomers. These monomer molecules enter the
deposition chamber 14 and coat all the surfaces within the chamber,
including the assembled microchip devices 12. A cold trap 24
collects any parylene flowing to the vacuum pump. This process also
can be adapted to vapor deposit polymers other than parylenes, but
which may have chemistries similar to that of parylenes.
[0082] It may be desired to increase the barrier properties of the
parylene or other coating material by making a multi-laminate
coating. In a preferred embodiment, a metal film, such as aluminum,
is evaporated or sputtered onto a first layer of parylene. Another
layer of parylene is then deposited onto the metal layer to
maintain the biocompatibility of the multi-laminate film. In this
embodiment, the first layer of parylene electrically insulates the
microchip from the metal layer, the metal layer serves as a barrier
to most liquids and vapors, and the outer parylene layer forms a
more biocompatible interface with the surrounding environment (e.g.
for implantable devices).
[0083] Other techniques one could use to conformally coat a
microchip device include plating, spin coating, dip coating, and
spraying. These may not be preferred, for example due to a need to
cure certain coating material, the need to use solvents or heat, as
well as the difficulty in achieving a truly conformal coating on
devices having varied topography.
[0084] (b) Patterning of the Conformal Coating
[0085] In a preferred embodiment, the microchip is fabricated and
the electrodes are masked. The microchip is then assembled to make
the electrical connections, if necessary, for actively controlled
microchips. The reservoirs can then be filled with molecules or
devices. Parylene is then vapor deposited over the whole device and
the masking covering the electrodes is removed. See FIG. 3, which
illustrates these process steps. In another embodiment, the
electrodes are not masked and parylene is selectively removed by a
laser, plasma, or by another etching method after deposition.
[0086] It is possible that in another embodiment, a heated resistor
or resistive material could be utilized to limit or prevent
deposition of the coating material to selected areas of the
microchip device--such as the reservoir caps. For example, a
resistor or resistive material could be deposited under or near
metal reservoir caps and etched away from the reservoirs. Parylene
could then be deposited in two steps: First to the front of the
substrate before reservoir filling and then to the back of the
substrate after reservoir filling. The reservoir cap, such as a
gold membrane, could be heated (e.g., to 150.degree. C.) by
applying a voltage to the resistors. If the heating can be
controlled, it would prevent parylene from depositing on the
reservoir cap. After assembling and filling, a second layer of
parylene could be deposited onto only the back of the microchip,
sealing the reservoirs and the package.
[0087] The methods described in U.S. Pat. Nos. 5,797,898 and
6,123,861, both to Santini et al., can be used to process the
microchip devices prior to parylene coating. A mask may be used to
protect the portion of the gold electrodes, which form the
reservoir caps, from becoming coated with parylene. In a preferred
embodiment, a physical mask, such as tape, can be positioned to
cover the face of the microchip, or a coating such as photoresist
or polyimide can be deposited and patterned over the electrodes.
Parylene does not adhere well to gold, so the parylene can be
readily removed, e.g., physically, if any is inadvertently
deposited on the gold membrane surface.
[0088] If a physical mask is used to protect the reservoir barrier
layers from parylene coating, then the parylene over the masked
area can be removed, for example by cutting the mask away. If the
microchip is not masked prior to the parylene deposition, then the
microchip can be masked and the parylene removed by etching. One
potential method of etching the parylene is by exposure to an
oxygen plasma (i.e. oxygen is ionized under vacuum by RF power to
create a plasma). The plasma reacts with the parylene to form
carbon dioxide gas and water vapor, which are removed by the
vacuum. The etching time is dependent upon the RF power and the
temperature. An alternative method of etching parylene involves
using a focused laser machining system. Most commercially available
excimer lasers have relatively large beam sizes (e.g., 8.times.25
mm, 2.times.2 mm), and thus a mask would be required. The etching
process would typically would involve the placement of a UV
resistant mask above the microchip to define the area for the
parylene to be removed. Then an excimer laser process would be used
to remove parylene with high precision and sharp edge definition.
Other types of lasers, such as a carbon dioxide laser, also could
be used if they have sharp enough resolution to make the desired
opening in the conformal coating.
[0089] To prepare the mask for selective removal from over the
reservoir caps, one needs to define small windows in the masking
material. In one embodiment, the steps for making such windows
might include (1) evaporating or sputter coating the parylene film
with a metal film such as aluminum or chromium; (2) coating the
metal film with photoresist and patterning the resist with standard
photolithographic methods to expose the metal in regions where the
parylene windows will be formed; and (3) etching the exposed metal
away using a suitable etchant. The parylene can then be removed
with an oxygen plasma, which will also remove the remaining
photoresist. The metal mask can then be removed by etching.
[0090] III. Functions and Uses of the Conformal Coatings
[0091] Both in vitro and in vivo applications of microchip delivery
systems can benefit from conformal coatings. For example, the
conformal coating can seal a drug in the reservoirs of a microchip
without trapping air in the reservoirs, which can inhibit drug
release. Conformal coating with parylene can also be applied to
individually seal filled reservoirs, so that multiple drugs can be
deposited and remain separated in a single microchip. In
particular, the conformal coating advantageously seals electrical
connections, so that the microchip device is electrically insulated
from the fluid surrounding, or in contact with, the microchip. For
in vivo applications, the conformal coating beneficially provides a
biocompatible surface on the implanted device.
[0092] Sealing the Electrical Connections
[0093] For some active microchip devices, leads must be attached to
the microchip to make electrical connections. This is accomplished
by first attaching the microchip to a carrier such as a printed
circuit board or plastic or ceramic carriers. Connections can then
be made between the microchip and the carrier using wire bonds, as
is commonly done in the integrated circuit industry. Additional
wires can be attached to the carrier to make electrical connections
to other circuits, components, carriers, or devices. In one
embodiment, attachment of leads to the microchip can be carried out
either before or after filling the reservoirs of the microchip with
the drug or placing other materials or components in the
reservoirs. In an alternative embodiment, a lead attachment method
uses "flip chip" technology, which involves attaching the leads by
reflowing solder bumps. Because this method involves the
application of heat, it would have to be used before the microchip
has been filled, in order to prevent damage to the drug or other
components in the reservoirs. It is understood that one skilled in
the art could use other standard integrated circuit packaging
methods, as described, for example, in Lau & Lee, Chip Scale
Package (McGraw-Hill, New York, N.Y. 1999).
[0094] Biocompatible Coatings
[0095] The microchip device desirably is provided with a
biocompatible coating for implantation applications. Parylene can
provide a biocompatible surface for implantation. Various
manufacturers supplying coatings and coating equipment indicate
that Parylene N and Parylene C have been tested for Acute Systemic
Toxicity, Intracutaneous Toxicity and Implantation and are
certified to comply with the USP biological testing requirements
for classification VI (Specialty Coating Systems, Indianapolis,
Ind., USA; see e.g., http://www.scscookson.com/applications-
/medical.htm). Parylene is not vulnerable to hydrolytic breakdown
in an implantation environment because it has a polymeric backbone
made up of carbon. Parylene C has been found to be compatible with
living cells and cells will proliferate on coated surfaces.
(Specialty Coating Systems, Indianapolis, Ind., USA; see e.g.,
http://www.scscookson.com/applications- /medical.htm).
[0096] IV. Use of the Microchip Devices and Systems
[0097] The microchip device systems can be used in a wide variety
of applications. The applications can be ex vivo or in vitro, but
more preferably are for in vivo applications, particularly
following non- or minimally-invasive implantation.
[0098] Preferred applications for using the devices and systems
include the controlled delivery of a drug to sites within the body
of a human or animal, biosensing, or a combination thereof. The
microchip systems are especially useful for drug therapies in which
it is desired to control the exact amount, rate, and/or time of
delivery of the drug. Preferred drug delivery applications include
the delivery of potent compounds, including both small and large
molecules, such as hormones, steroids, chemotherapy medications,
vaccines, gene delivery vectors, and some strong analgesic
agents.
[0099] The microchips can be implanted into the body of a human or
other animal via surgical procedures or injection, or swallowed,
and can deliver many different drugs, at varying rates and varying
times. In another embodiment, the microchip device includes one or
more biosensors (which may be sealed in reservoirs until needed for
use) that are capable of detecting and/or measuring signals within
the body of a patient. As used herein, the term "biosensor"
includes, but is not limited to, sensing devices that transduce the
chemical potential of an analyte of interest into an electrical
signal, as well as electrodes that measure electrical signals
directly or indirectly (e.g., by converting a mechanical or thermal
energy into an electrical signal). For example, the biosensor may
measure intrinsic electrical signals (EKG, EEG, or other neural
signals), pressure, temperature, pH, or loads on tissue structures
at various in vivo locations. The electrical signal from the
biosensor can then be measured, for example by a
microprocessor/controller, which then can transmit the information
to a remote controller, another local controller, or both. For
example, the system can be used to relay or record information on
the patient's vital signs or the implant environment, such as blood
gases, drug concentration, or temperature.
[0100] The system also has a variety uses that are not limited to
implantation. For example, the reservoir contents may include a
sensor for detecting a chemical or biological molecule at the site
in which the microchip is placed, and the telemetry system
transmits a status of the sensor detection to the remote
controller. Such a site could be in vivo or in vitro. The chemical
or biological molecule could, for example, be associated with a
chemical or biological weapon, and the system used in an early
warning/detection system.
[0101] Active microchip devices may be controlled by local
microprocessors or remote control. Biosensor information may
provide input to the controller to determine the time and type of
activation automatically, with human intervention, or a combination
thereof. The microchip devices have numerous in vivo, in vitro, and
commercial diagnostic applications. The microchips are capable of
delivering precisely metered quantities of molecules and thus are
useful for in vitro applications, such as analytical chemistry and
medical diagnostics, as well as biological applications such as the
delivery of factors to cell cultures.
[0102] The invention can further be understood with reference to
the following non-limiting examples.
EXAMPLE 1
Tape Masking and Parylene Coating a Microchip Device
[0103] This example is described with reference to FIG. 3. A
microchip device substrate 10 with reservoirs 12 and gold membrane
reservoir caps 14 were prepared using fabrication processes
described in U.S. Pat. No. 6,123,861, to Santini, Jr. et al. The
front of the microchip substrate, except for the wire bond pads,
were masked with a water-soluble tape 16, 3M Mask Plus II Water
Soluble Wave Solder Tape No. 5414. The tape 16 served to protect
the microchip during assembly and to mask the front of the
microchip during parylene coating. The microchip was attached to an
assembly consisting of a cable soldered to a printed circuit board
carrier (not shown). Connections 18 were made from the bond pads on
the microchip to the bond pads on the board using a wire bonder. In
this experiment, these wire bonds were protected with epoxy so the
microchip could be turned over and leads could be soldered to the
back of the printed circuit board. (In actual practice, the
parylene or other conformal coating, rather than epoxy, would
protect and insulate the wire bonds, if wire bonds were to be
used.) The microchip was then filled with a drug 20. The assembled
device was then coated in a layer of vapor deposited parylene 22,
including the wire bonds and the solder joints. The parylene was
scored around the edge of the tape 16, and the tape was removed.
Finally, the microchip was soaked in water to remove the
water-soluble adhesive from the face of the microchip, leaving
exposed reservoir caps 24.
EXAMPLE 2
Parylene Coating Followed by Selective Laser Removal
[0104] This example is described with reference to FIG. 4. The
microchip device substrate 10 with reservoirs 12 and gold membrane
reservoir caps 14 would be manufactured and mounted to a
flexible-circuit carrier as described in Example 1. The connections
18 would be made by wirebonding the microchip bond pads to the
exposed leads on the flex circuit. The wirebonds would be protected
during reservoir filling. The reservoirs 12 would then filled with
a drug 20, and then a wax layer 26 would then added to fill the
remaining volume of the reservoirs 12 over the drug 20 before
sealing the reservoirs 12 of the device. The entire microchip
device package would then conformally coated with parylene 22,
consequently sealing reservoirs 12. A contact mask (not shown),
which would be made of a metal or another excimer laser-resistant
material, would then be placed over the face 28 of the
parylene-coated microchip device. A laser would then be directed to
selectively ablate the parylene or to cut the parylene around the
edges of the reservoir caps to expose the reservoir caps 24.
EXAMPLE 3
Improved Barrier Properties with a Metal Film
[0105] This example is described with reference to FIG. 5. The
microchip device substrate 10 with reservoirs 12 and gold membrane
reservoir caps 14 would be manufactured as described in Example 1.
This microchip device substrate would then be mounted to a package
that has solder bumps placed in a pattern that matches the bond
pads on the microchip. The microchip and package would then be
brought into contact with each other and the solder bumps heated so
they reflow and make electrical connection. The reservoir caps 14
would then be masked. Then the reservoirs would be filled with a
drug 20. Next, a first layer 32 of parylene would be conformally
coated onto the assembled microchip device. Then a layer of metal
film 34, such as aluminum, would be evaporated or sputtered over
first parylene layer 32 to form an impermeable barrier. An outer
layer 36 of parylene would then be conformally coated over the
metal film 32 to provide a biocompatible outer layer for the
microchip device. The mask 30 would then be removed. If a masking
tape were to be used, then the parylene/metal layers (32/34/36)
would first be scored to facilitate separation only over the
reservoir caps 14, leaving the remaining coating structure
intact.
[0106] This laminate structure approach also could be used to seal
the reservoir openings (distal the reservoir caps) after the
reservoirs are filled with the drug. If needed, a buffer layer,
such as the wax layer described in Example 2, could be included.
Then the back side of the substrate would be coated with parylene
or another vapor depositable coating material. Using a patterning
method, such as masked plasma etching, the parylene would be
selectively removed from the backside surfaces between the
reservoirs. Then a metal film would be deposited to coat the
parylene over the drug and the substrate between the reservoirs. A
second coat of parylene would then be deposited over the metal
film. This approach provides a barrier between the reservoirs, so
that once the drug is released from a reservoir and the opened
reservoir becomes filled with fluid (e.g., bodily fluids), the
metal film reduces the vapor transmission to adjacent
reservoirs.
[0107] Publications cited herein and the materials for which they
are cited are specifically incorporated by reference. Modifications
and variations of the methods and devices described herein will be
obvious to those skilled in the art from the foregoing detailed
description. Such modifications and variations are intended to come
within the scope of the appended claims.
* * * * *
References